A breakthrough in improving stroke treatment
Ischemic stroke occurs when there is a sudden interruption of blood flow to the brain, usually caused by a clot in a blood vessel. The most effective drug treatment for acute ischemic stroke is tissue plasminogen activator, tPA, an enzyme that breaks up clots. However, tPA must be given within 3 hours after the onset of symptoms because tPA itself can lead to bleeding in the brain. As a result, more than 90% of stroke patients cannot be treated with tPA. Furthermore, tPA may have other harmful side effects such as seizures, damage to brain cells, and breaking down the normally impermeable blood-brain barrier.
In the July 2008 issue of Nature Medicine, Drs. Christer Betsholtz and Ulf Eriksson of the Karolinska Institutet in Stockholm, Sweden, along with colleagues from Michigan, Maryland and Georgia, show that an existing cancer treatment may help overcome the limitations of tPA. Drs. Betsholtz and Eriksson are members of the Transatlantic Network of Excellence for the Identification of Novel Genetic Targets in Hemorrhagic Stroke. The research was also supported by the National Institutes of Health, the Karolinska Institutet, the Novo Nordisk Foundation, the Swedish Research Council, the Swedish Cancer Foundation, and the Inga-Britt and Arne Lundberg Foundation.
In their article, the researchers studied the action of tPA in a mouse model of ischemic stroke. They found that tPA causes a breakdown of the blood-brain barrier through its action on the platelet derived growth factor-CC (PDGF-CC) pathway. In fact, breaking up clots is only one of tPA’s enzymatic actions. tPA also converts an inactive form of PDGF-CC to an active form, which then activates the PDGF-α receptor. When the team injected mice with antibodies against PDGF-CC along with tPA, the breakdown in the blood-brain barrier was prevented. The same effect was seen when the animals were treated with imatinib mesylate, an inhibitor of PDGF-α. In fact, imatinib pre-treatment before the administration of tPA substantially reduced bleeding complications and brain damage, even when tPA was given 5 hours after the onset of ischemic stroke. Importantly, blocking the PDGF-CC/PDGFR-α pathway with imatinib did not appear to interfere with tPA’s ability to break up clots.
Imatinib is a oral drug currently used to treat chronic myelogenous leukemia and other cancers. Could simply taking a pill widen the therapeutic window for safe tPA administration? The researchers hope to find out, planning a randomized controlled clinical trial to test the feasibility and safety of imatinib in ischemic stroke
Click on the title to access the article in Nature Medicine: Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke.